Abstract 1467: Vascular Endothelial Cell-Specific Suppression of NF-κB Activity Attenuates Hypertension-Induced Cardiovascular End Organ Damage
BACKGROUND: NF-κB has been implicated in hypertension-induced vascular injury and Angiotensin II-induced signal transduction. Although the previous use of NF-κB inhibitors supports a causal role in vascular injury these drugs are not specific. Thus, our aim is to study the in vivo role of NF-κB in hypertension-induced cardiovascular and renal end organ damage.
METHODS and RESULTS: Using the Cre/lox technique, we have generated mice with vascular endothelial cell-restricted expression of the NF-κB super-repressor IκBαΔN (=ΔNTie1). Expression of IκBαΔN and reduced NF-κB activity in endothelial cells was confirmed by using primary cell cultures. Mice were put on a high sodium diet and simultaneously treated with the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME) and Ang II via osmotic mini pumps during 14 days. This treatment resulted in a strong cardiac and renal end organ damage in terms of cardiac hypertrophy (p<0.05), elevated albuminuria (p<0.05) and characteristic histological changes of heart and kidney, when compared to sham operated animals. In contrast, ΔNTie1 mice displayed an attenuated cardiovascular end organ damage compared to control mice (n>=15 for each group). We measured diminished albuminuria in ΔNTie1 mice (p<0.05). A reduced heart weight was observed in these mice as well (p<0.05). When analysing potential NF-κB target genes, RT-PCR showed significantly reduced expression of important early atherogenic markers such as VCAM and MCP-1 in kidneys of treated ΔNTie1 mice compared to control mice (p<0.05). The regulation of these atherogenic markers by NF-κB additionally supports the role of endothelial NF-κB in the development of cardiovascular end organ damage.
CONCLUSION: Our results indicate that targeted inhibition of NF-κB in vascular endothelial cells is a potential tool to reduce hypertension-induced cardiovascular end organ damage. We are showing direct genetic in vivo relevance of NF-κB, establishing a causal link between NF-κB activation in vascular endothelial cells and hypertension-induced end organ damage.